Bone remodeling, the mechanism whereby vertebrates renew bone tissues throughout adulthood, comprises two phases: resorption of preexisting mineralized bone matrix by a specialized cell type, the osteoclast, followed by de novo bone formation by another specialized cell type, the osteoblast. Genetic and molecular studies have shown that local effectors (cytokines and growth factors) and systemic effectors (hormones and neuromediators) modulate both phases of bone remodeling.
One of the most intensively studied genes regulating bone remodeling is LDL-receptor related protein 5 (LRP5). Loss-of-function mutations in LRP5 result in osteoporosis pseudoglioma (OPPG), a disease characterized by severe bone loss due to a decrease in bone formation and by the persistence of embryonic vascularization of the eyes, causing blindness. By contrast, gain-of-function mutations in LRP5 cause another bone disease, high bone mass syndrome. The involvement of Lrp5 in two human diseases of opposite nature underscores the importance of the pathways controlled by this gene in the regulation of bone formation. However, the mechanism by which LRP5 affects bone development is not known.
Mice genetically deficient for the TPH1 gene (“knockout mice”) have been reported. In one case, the mice reportedly expressed normal amounts of serotonin in classical serotonergic brain regions, but largely lacked serotonin in the periphery. In another, the knockout mice exhibited abnormal cardiac activity, which was attributed to a lack of peripheral serotonin (Côté et al., 2003, Proc. Natl. Acad. Sci. USA 100:13525-13530).
International Patent Application No. PCT/US2009/038817, published as WO 2009/123978, the disclosure of which is incorporated herein in its entirety, is directed to methods of diagnosing, preventing, and treating bone mass diseases using therapeutic agents for lowering or increasing serum serotonin levels. International Patent Application No. PCT/US2009/064383, published as WO 2010/056992, the disclosure of which is incorporated herein in its entirety, is also directed to methods of diagnosing, preventing, and treating bone mass diseases using therapeutic agents for lowering or increasing serum serotonin levels.